2-(benzyloxyalkyl)-4-phenylimino-1, 3-cyclopentanedione derivatives



United States Patent 3,278,599 2-(BENZYL0XYALKYL)-4-PHENYLIMIN0-1,3-CYCLOPENTANEDIONE DERIVATIVES Gerhard R. Wendt, Havertown, and Kurt W.Ledig, Philadelphia, Pa., assignors to American Home ProductsCorporation, New York, N.Y., a corporation of Delaware No Drawing. FiledMar. 13, 1964, Ser. No. 351,816

2 Claims. (Cl. 260-566) This invention is concerned with novelZ-benzyloxyalkyl-4-phenylimino-1,3-cyclopentanediones havingantibacterial activity, and with intermediates occurring in theirsynthesis.

The claimed compounds have the following general formula:

i =0 ll- C) wherein X is hydrogen, lower alkyl, lower alkoxy, halogen,halo(lower)alkyl or nitro; X is hydrogen, lower alkyl, lower alkoxy,halogen, halo(lower)-alkyl, nitro or carb-oxy. It is intended that X andX" may be in the 0-, m-, or p-positions.

Preferred compounds are those in which X and X are hydrogen.

The claimed intermediates which are first formed in the synthesis of theabove compounds are 3-(2-benzyloxy alkyl)-1,2,4-cyolopentanetrioneshaving the formula:

OCH 2M where X is as above defined.

The claimed compounds are prepared as shown below by reacting a5-benzyloxy-2-pentanone (II), the synthesis of which is givenhereinafter, with ethyl oxalate to form a3-(2-benzyloxyalkyl)-1,2,4-cyclopentanetrione (III).

This reaction is carried out under anhydrous conditions in the presenceof a basic condensation agent such as, for example, but withoutlimitation, sodium methylate. The initial mixing of the reactants takesplace below room temperature; following which, the reaction mixture isrefluxed for over an hour, acidified, and again refluxed for over 2hours. The reaction mixture is neutralized with base and the resultingsalt is filtered off. The filtrate containing the3-(2-benzyloxyalkyl)-1,2,4-cyclopentanetrione (III) is treated with ananilino compound (IV) in acid medium. The reaction mass then is dilutedwith water to precipitate the product (I).

X COOEt (III) 3,278,599 Patented Oct. 11, 1966 l o X The starting5-benzyloxy-2-pentanone (II) is prepared by reacting in ether methylmagnesium bromide with a 4-benzyloxybutynonitrile. This reactionpreferably is carried out at the reflux temperature of the reaction massfor over two hours. Following this reaction time, the mixture is pouredinto ice water and acidified. An organic layer thereupon forms, which iswashed and dried to yield an oil mixed with solvent. Distillation of thesolvent yields the required starting material.

The following specific examples serve to illustrate but are not intendedto limit the scope of the present invention.

EXAMPLE I Preparation 0 S-benzyloxy-Z-pentanone To 180 ml. of a 3 molarsolution of methyl magnesium bromide in either, was added, whilestirring and refluxing, a solution of 48.0 g. of4-benzyl-oxybutyronitrile as prepared by the method of G. M. Bennett andA. L. Hock, J. Chem. Soc. 472 (1927), in 50 ml. of ether over a periodof 30 minutes.

The reaction mixture was refluxed for another 2 hours, poured intoice-water and made acidic with 2 N sulfuric acid. The organic layer wasseparated, washed with a saturated sodium bicarbonate solution anddried. The oil obtained on evaporation of the solvent was distilled,affording the title compound, B.P. 104-107 (0.1 mm.).

IR 5.83 r. (Found: C, 74.76; H, 8.62. C H O requires: C, 74.97; H,8.39%.)

EXAMPLE 2 Preparation of Z-(Z-benzyloxyethyl)-4-phenylimino-1 ,3-

cyclopentanedione To a suspension of 418 ml. of abs. alcohol and 46.8 g.of sodium methylate was added at 5 a solution of 138 g. of ethyl oxalateand 83 g. of S-benzyloxy-Z-pentanone while stirring. After the addition,the reaction mixture was refluxed for 1.5 hours, acidified with 4 Nsulfuric acid and then refluxed for another 2.5 hours. The reactionmixture was adjusted to pH 7 with 50% sodium hydroxide and the saltfiltered off. The filtrate containing 3 (2 benzyloxyethyl) 1,2,4cyclopentanetrione was treated with 50 ml. of 2 N hydrochloric acid andml. of aniline, followed by the addition of 700 ml. of water, and theresulting precipitate filtered and triturated EXAMPLE 3 Preparation f 2-(Z-p-ch lorobenzy loxyethyl-4-(pcarboxyphenylimino)-1,3-cycl0pentanedi0ne Using 5 (pchlorobenzyloxy) 2 pentanone in place of 5 benzyl'oxy 2 pentanone and paminobenzoic acid in place of aniline but otherwise carrying out thereaction as described in the previous example, the title compound isobtained.

When tested phar- When applying the above procedure to the startingcompounds listed below the products hereinafter listed are obtained:

Starting Materials Products 5-(m-Methoxybenzyloxy)-2-pentanone andp-nitroaniline.

5-(p-Trifiuoromethylbenzyloxy)- 2-pentan0ne and p-bromoaniline.

5-(o-Butylbenzyloxy)'2-pentan0ne and o-butylaniline.

5-(p-Methylbenzyloxy)-2-pentanone and p-methoxyaniline.

5-(p-N itrobenzyloxy)-2-pentanone and p-butoxyaniline.

3-(2m-Methoxybenzyloxyethyl)- 1,2,4-cyclopentanetrione, 2-(2-m-Methoxybenzyloxyethyl) -4- (p-nitrophenylimino)-1,3-cyclopentanedione.

3-(2-o-Butoxybenzyloxyethyl)- 1,2,4-eycl0pentanetri0ne; 2-(2-0-Butoxybenzyloxyethyl)-4(Indichloromethylphenylimino)-l,3-cyclopentanedione.

3-(2-p-Trifluor0methy1benzyloxyethyl)-1,ZA-cyclopentanetrione;2-(2-p-TrifluoromethylbenzyloxyethyD-4-(p-bromophenyli1nino)-1,3cyclopentanedione.

3-(2-o-Butylbenzyloxyethyl)-l,2,4- cyclopentanetrione; 2-(2-o-Buty1-benzyloxyethyD-4-(o-butyL pheny1imin0)-1,3-cyc1opentanedione.

3-(2-p-Methy1benzyloxyethyl)- 1,2,4-cyclopentanetrione; 2-(2-p-Methylbenzyxyethyl)-4(pmethoxypheny1iInino)-1,3-cycl0 pentanedione.

3- (2p-Nitrobenzyloxyethyl) -1, 2,4-

cyclopentanetrione; 2-(2-p-Nitrobenzyloxyethyl)-4-(pbutoxyphenylimino)-1,3-cyelopentancdione.

Starting Materials Products 5-(o-Ethylbenzyloxy)-2-pentanone 3-(2-o-Ethylbenzyloxyeth y1)- and p-tolylaniline.

1,2,4cyclopentanetrione; 2-(2-0-Ethylbenzyloxyethyl)-4-(p-tolylpheny1imino)-l,3-cyclopentanedione.

The compounds of this invention can be administered withpharmaceutically acceptable inert carriers in a wide variety of oral orparenteral unit dosage forms containing 25, 100, 250 or 500 mg. of theactive ingredients for the symptomatic adjustment of the dosage, or inadmixture with other active compounds.

The present invention also includes the process of bringing thecompounds thereof into a form suitable for therapeutic administration byassociating them with liquid or solid, pharmaceutically acceptablecarriers.

What is claimed is:

1. A compound of the formula:

wherein X is selected from the group consisting of hydrogen, loweralkyl, lower alkoxy, chloro, bromo, dichloromethyl, trifluoromethyl andnitro and X is selected from the group consisting of hydrogen, loweralkyl, lower alkoxy, halogen, halo(lower)alkyl, nitro and carboxy.

2. 2 (2 benzyloxyethyl) 4 phenylimino 1,3- cyclopentanedione.

No references cited.

CHARLES B. PARKER, Primary Examiner. ROBERT V. HINES, AssistantExaminer.

1. A COMPOUND OF THE FORMULA: